Issue 29, 2022

Highly stereoselective and enantiodivergent synthesis of cyclopropylphosphonates with engineered carbene transferases

Abstract

Organophosphonate compounds have represented a rich source of biologically active compounds, including enzyme inhibitors, antibiotics, and antimalarial agents. Here, we report the development of a highly stereoselective strategy for olefin cyclopropanation in the presence of a phosphonyl diazo reagent as carbene precursor. In combination with a ‘substrate walking’ protein engineering strategy, two sets of efficient and enantiodivergent myoglobin-based biocatalysts were developed for the synthesis of both (1R,2S) and (1S,2R) enantiomeric forms of the desired cyclopropylphosphonate ester products. This methodology enables the efficient transformation of a broad range of vinylarene substrates at a preparative scale (i.e. gram scale) with up to 99% de and ee. Mechanistic studies provide insights into factors that contribute to make this reaction inherently more challenging than hemoprotein-catalyzed olefin cyclopropanation with ethyl diazoacetate investigated previously. This work expands the range of synthetically useful, enzyme-catalyzed transformations and paves the way to the development of metalloprotein catalysts for abiological carbene transfer reactions involving non-canonical carbene donor reagents.

Graphical abstract: Highly stereoselective and enantiodivergent synthesis of cyclopropylphosphonates with engineered carbene transferases

Supplementary files

Article information

Article type
Edge Article
Submitted
05 Apr. 2022
Accepted
06 Maijs 2022
First published
06 Jūn. 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 8550-8556

Highly stereoselective and enantiodivergent synthesis of cyclopropylphosphonates with engineered carbene transferases

X. Ren, A. L. Chandgude, D. M. Carminati, Z. Shen, S. D. Khare and R. Fasan, Chem. Sci., 2022, 13, 8550 DOI: 10.1039/D2SC01965E

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